This P01 application will focus on a variety of targeted immunotherapy approaches for the treatment of B-cell malignancies, such as non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM), and chronic lymphocytic lymphoma (CLL). It is comprised of 3 preclinical projects and one clinical project, which are supported by 6 cores. This program project represents a collaboration of three institutions along with additional collaborations and advice of leading experts in each of the research areas. A number of antigen targets will be examined: CD20, CD22, CD74, and HLA-DR because these appear to be the most promising from our own published studies and those of others, and because we now have access to humanized (CDR-grafted) forms of these antibodies. The overall goal is to develop immunotherapy strategies for the more effective, targeted therapy of these neoplasms with one or more of these MAbs, in one or more forms (unlabeled, radiolabeled, and/or drug conjugated), and to be used alone or in combination with other modalities. Of particular interest is the rapid translation of basic and preclinical studies to the clinic. In this regard, 2 clinical protocols, one using a combination of 90Y-humanized anti-CD22 IgG with Rituxan and another utilizing a recombinant bispecific antibody pretargeting approach are planned. However, the immediate goals of this project are to better understand how these various reagents can function alone or in certain combinations for the more effective therapy of B-cell malignancies and to gain a better understanding of the mechanisms involved in their actions, in tumor resistance, and in predicting which tumor types will respond best. Collectively, the integration of all of these different, but related endeavors promises to provide new knowledge and strategies for the improved management of B-cell malignancies.